What factors do you consider when determining treatments for patients like this who are BRAF mutated?
The factors to think about are disease burden, LDH, and the desire of the patient to deal with toxicity, because that is often a big issue. This is a patient who was intermediate, meaning there was an intermediate disease burden, although the LDH was normal and they could have gone either way. You could have reasonably put someone like this on BRAF/MEK inhibition, or you could have put them on immunotherapy. It all depends on the patient’s individual choice that makes the difference.
Is the durable response for this individual typical for a patient with a low disease burden? Would it be safe to tell the patient to stop therapy if she is in stable, complete remission?
With BRAF/MEK inhibition, it’s always tough to decide when to stop therapy. With almost all targeted therapies of this kind in solid tumors, you should basically treat them until they progress.
I would not feel comfortable telling someone like this, if they were tolerating the drug well, to stop treatment. Durable response would not be atypical for someone with a low disease burden, or a moderate disease burden and a normal LDH who has what looks like just a modest amount of total disease.
How do we factor in this patient’s LDH, sites of disease, and age in predicting the likelihood of achieving a durable response, as she experienced?
Usually the younger patients will have V600E, rather than V600K, which means they have a greater chance for a long-term response. And, with the low LDH and the modest disease burden, those are the patients who will do well long term.
The high disease burden patients always get treated with BRAF/MEK inhibition upfront to get that quick response, but those are often the patients who, because of their disease burden, don’t do well in the long term. It’s ironically the lesser disease burden patients who usually get immunotherapy. But, when treated with BRAF/ MEK inhibition, they can do very well for a long period of time.
What factors do you consider when determining the initial treatment for patients like this who are symptomatic, have a high LDH and disease burden, and have a BRAF mutation?
In a patient like this who is symptomatic, most people would agree that you would be committed to going with BRAF/MEK up front, though some would consider an ipilimumab/ nivolumab (Opdivo) combo up front because you can see deep and rapid responses.
Would you consider switching to immunotherapy after achieving a good response?
Absolutely. The dirty little secret is that a lot of doctors will give 8 weeks of BRAF/MEK and, hopefully before they develop a resistance, will then switch to immunotherapy. Usually, it would be nivolumab and carry on from there after that initial induction of BRAF/MEK.
Interestingly, if you could reintroduce BRAF/ MEK, if there was a long interval where you had no evidence of progression, say on the immunotherapy and then 6 months, a year later, you could switch back to immunotherapy—that’s still an open question.